Two Forms of Astrocyte Calcium Excitability Have Distinct Effects on NMDA Receptor-Mediated Slow Inward Currents in Pyramidal Neurons

Shigetomi, Eiji; Bowser, David N.; Sofroniew, Michael V.; Khakh, Baljit S.

doi:10.1523/jneurosci.1717-08.2008

Cited by 238 publications

(261 citation statements)

References 42 publications

(62 reference statements)

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“…S1 F-G), together providing evidence for spatially compartmentalized spread of dendritically originating sSEPs. The frequency of these events was comparable with frequency of SICs reported in the literature (7,27) and did not vary significantly across the somatodendritic axis ( Fig. 1I and Fig.…”

Section: Resultssupporting

confidence: 87%

Active dendrites regulate the impact of gliotransmission on rat hippocampal pyramidal neurons

Ashhad

Narayanan

2016

Proc. Natl. Acad. Sci. U.S.A.

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An important consequence of gliotransmission, a signaling mechanism that involves glial release of active transmitter molecules, is its manifestation as N-methyl-D-aspartate receptor (NMDAR)-dependent slow inward currents in neurons. However, the intraneuronal spatial dynamics of these events or the role of active dendrites in regulating their amplitude and spatial spread have remained unexplored. Here, we used somatic and/or dendritic recordings from rat hippocampal pyramidal neurons and demonstrate that a majority of NMDAR-dependent spontaneous slow excitatory potentials (SEP) originate at dendritic locations and are significantly attenuated through their propagation across the neuronal arbor. We substantiated the astrocytic origin of SEPs through paired neuron-astrocyte recordings, where we found that specific infusion of inositol trisphosphate (InsP 3 ) into either distal or proximal astrocytes enhanced the amplitude and frequency of neuronal SEPs. Importantly, SEPs recorded after InsP 3 infusion into distal astrocytes exhibited significantly slower kinetics compared with those recorded after proximal infusion. Furthermore, using neuron-specific infusion of pharmacological agents and morphologically realistic conductance-based computational models, we demonstrate that dendritically expressed hyperpolarization-activated cyclic-nucleotide-gated (HCN) and transient potassium channels play critical roles in regulating the strength, kinetics, and compartmentalization of neuronal SEPs. Finally, through the application of subtypespecific receptor blockers during paired neuron-astrocyte recordings, we provide evidence that GluN2B-and GluN2D-containing NMDARs predominantly mediate perisomatic and dendritic SEPs, respectively. Our results unveil an important role for active dendrites in regulating the impact of gliotransmission on neurons and suggest astrocytes as a source of dendritic plateau potentials that have been implicated in localized plasticity and place cell formation.neuron-astrocyte interaction | NMDA receptors | HCN channels | transient potassium channels | plateau potentials G liotransmission, a signaling mechanism that involves glial release of active transmitter molecules, has been implicated in the regulation of several neurophysiological processes that include synaptogenesis, synaptic transmission and plasticity, neuronal excitability, and synchrony (1-3). An important consequence of gliotransmission is its manifestation as slow inward currents (SIC), events that are mediated by neuronal extrasynaptic N-methyl-D-aspartate receptors (NMDAR) and are concomitant to astrocytic calcium elevations (3-8). Although these well-studied events have provided us with important insights into tripartite neuron-astrocyte interactions (1-9), recordings of such SICs have focused predominantly on the soma despite the dendritic localization of a majority of synapses (10). Research over the past two decades has clearly established that dendritic processing critically contributes to neuronal physiology and is best assesse...

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Section: Resultssupporting

confidence: 87%

Active dendrites regulate the impact of gliotransmission on rat hippocampal pyramidal neurons

Ashhad

Narayanan

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Their data and ours are not necessarily contradictory and may simply reflect multiple Ca 2 þ targets within astrocytes as well as differential Ca 2 þ responses related to either receptor subtype or the location and duration of a Ca 2 þ response. For example, Shigetomi et al 27 found stimulation of both P2Y 1 Rs and proteinase-activated receptors (PAR-1s) increased intracellular Ca 2 þ in astrocytes, but only activation of PAR-1s resulted in significant release of glutamate from astrocytes and neuronal toxicity. Shigetomi et al 27 suggested that this was related to the modes of glutamate exocytosis triggered by these agonists, the spatial location of the glutamate release sites or the duration of the Ca 2 þ transients.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, we found no evidence that stimulation of P2Y 1 Rs induced significant, Ca 2 þ -sensitive glutamate release from astrocytes, and consequently, its stimulation may not generate excitotoxic NMDA receptormediated inward currents in neurons. 27 Kazuhide Inoue and coworkers 34 have reported that stimulation of P2Y 1 Rs enhances long-term neuroprotection by upregulating oxidoreductase genes and stimulating interleukin 6 release. They also reported long-term neurodestructive effects after P2Y 1 R stimulation that appeared linked to a p-RelA-mediated NF-kB pathway that modulated the transcriptional activity of cytokine/ chemokine.…”

Section: Discussionmentioning

confidence: 99%

P2Y₁R-Initiated, IP₃R-Dependent Stimulation of Astrocyte Mitochondrial Metabolism Reduces and Partially Reverses Ischemic Neuronal Damage in Mouse

Zheng

Watts

Holstein

et al. 2013

J Cereb Blood Flow Metab

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Glia-based neuroprotection strategies are emerging as promising new avenues to treat brain damage. We previously reported that activation of the glial-specific purinergic receptor, P2Y 1 R, reduces both astrocyte swelling and brain infarcts in a photothrombotic mouse model of stroke. These restorative effects were dependent on astrocyte mitochondrial metabolism. Here, we extend these findings and report that P2Y 1 R stimulation with the purinergic ligand 2-methylthioladenosine 5 0 diphosphate (2MeSADP) reduces and partially reverses neuronal damage induced by photothrombosis. In vivo neuronal morphology was confocally imaged in transgenic mice expressing yellow fluorescent protein under the control of the Thy1 promoter. Astrocyte mitochondrial membrane potentials, monitored with the potential sensitive dye tetra-methyl rhodamine methyl ester, were depolarized after photothrombosis and subsequently repolarized when P2Y 1 Rs were stimulated. Mice deficient in the astrocyte-specific type 2 inositol 1,4,5 trisphosphate (IP 3 ) receptor exhibited aggravated ischemic dendritic damage after photothrombosis. Treatment of these mice with 2MeSADP did not invoke an intracellular Ca 2 þ response, did not repolarize astrocyte mitochondria, and did not reduce or partially reverse neuronal lesions induced by photothrombotic stroke. These results demonstrate that IP 3 -Ca 2 þ signaling in astrocytes is not only critical for P2Y 1 R-enhanced protection, but suggest that IP 3 -Ca 2 þ signaling is also a key component of endogenous neuroprotection.

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“…However, the exact pathway involved in this process is still under investigation. It has been shown that SIC frequency and amplitude increase upon activation of astrocytic G-protein coupled receptors (GPCRs) in the hippocampus [50,51], such as PAR1 receptors [53]. Concomitantly, stimulating the PAR1 receptor on astrocytes was recently shown to trigger calcium-dependent release of glutamate through Best1 channels in the hippocampus [64][65][66].…”

Section: Agonist Control Of Nmdar At Extrasynaptic Sitesmentioning

confidence: 99%

Organization, control and function of extrasynaptic NMDA receptors

Papouin

Oliet

2014

Phil. Trans. R. Soc. B

154

123

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N-methyl D-aspartate receptors (NMDARs) exist in different forms owing to multiple combinations of subunits that can assemble into a functional receptor. In addition, they are located not only at synapses but also at extrasynaptic sites. There has been intense speculation over the past decade about whether specific NMDAR subtypes and/or locations are responsible for inducing synaptic plasticity and excitotoxicity. Here, we review the latest findings on the organization, subunit composition and endogenous control of NMDARs at extrasynaptic sites and consider their putative functions. Because astrocytes are capable of controlling NMDARs through the release of gliotransmitters, we also discuss the role of the glial environment in regulating the activity of these receptors.

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Two Forms of Astrocyte Calcium Excitability Have Distinct Effects on NMDA Receptor-Mediated Slow Inward Currents in Pyramidal Neurons

Abstract: Astrocytes display excitability in the form of intracellular calcium concentration ([Ca2ϩ

Cited by 238 publications

References 42 publications

Active dendrites regulate the impact of gliotransmission on rat hippocampal pyramidal neurons

Active dendrites regulate the impact of gliotransmission on rat hippocampal pyramidal neurons

P2Y₁R-Initiated, IP₃R-Dependent Stimulation of Astrocyte Mitochondrial Metabolism Reduces and Partially Reverses Ischemic Neuronal Damage in Mouse

Organization, control and function of extrasynaptic NMDA receptors

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Two Forms of Astrocyte Calcium Excitability Have Distinct Effects on NMDA Receptor-Mediated Slow Inward Currents in Pyramidal Neurons

Abstract: Astrocytes display excitability in the form of intracellular calcium concentration ([Ca2ϩ

Cited by 238 publications

References 42 publications

Active dendrites regulate the impact of gliotransmission on rat hippocampal pyramidal neurons

Active dendrites regulate the impact of gliotransmission on rat hippocampal pyramidal neurons

P2Y1R-Initiated, IP3R-Dependent Stimulation of Astrocyte Mitochondrial Metabolism Reduces and Partially Reverses Ischemic Neuronal Damage in Mouse

Organization, control and function of extrasynaptic NMDA receptors

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P2Y₁R-Initiated, IP₃R-Dependent Stimulation of Astrocyte Mitochondrial Metabolism Reduces and Partially Reverses Ischemic Neuronal Damage in Mouse